tbuckley/cabot-search huggingface dataset:
RTID-01. A RANDOMIZED STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION FOR BRAIN METASTASIS FROM NON-SMALL CELL LUNG CANCER (LIMITLESS)
Authors: Manmeet Ahluwalia, Michael McDermott, Ahmad Ozair, Atulya Khosla, Arjun Sahgal, Mark V Mishra, Achal Achrol, K Singh Sahni, Nader Sanai, Nir Lipsman, Graeme F Woodworth
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Blood-brain barrier disruption (BBBD) has been demonstrated, in preclinical models, to improve systemic drug delivery for BM. Low-intensity focused ultrasound (LIFU) with intravenously (IV) administered microbubble oscillators results in non-invasive BBBD, potentially permitting drug delivery. This randomized controlled trial (RCT) aims to determine the safety and efficacy of LIFU-mediated BBBD for NSCLC BM with immunotherapy. METHODS LIMITLESS is an ongoing prospective, multicenter, parallel-arm, open-label RCT that randomizes patients with NSCLC-BM on pembrolizumab monotherapy prescribed as per standard-of-care to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in 2:1 ratio. Included patients have age ≥18 years, normal organ function, KPS≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM, with ≥1 BM meeting measurable disease RANO-BM criteria. Patients on both arms receive standard-of-care therapy, while those on arm 1 also undergo LIFU before each dose of pembrolizumab (200 mg IV every 3 weeks). These patients undergo pre-treatment MRI brain, followed by IV administration of oscillating microbubbles for enhanced sonication. MR-guided BBBD is then performed using 220 kHz LIFU device with real-time acoustic feedback. Pembrolizumab is infused immediately thereafter, and repeat MRI done confirming BBB closure each cycle. Primary study endpoint is overall objective response rate (ORR) at 6 months as per RANO-BM criteria. Using a Bayesian design, a superior ORR of 60% is assumed for the LIFU arm versus 30% in the control arm for N = 96, 64 subjects in LIFU and 32 in control arm, for 80% power, with alpha = 0.05. For upper-bound estimate ORR of 45% in LIFU arm and 30% in control arm, the study needs N = 369 subjects; 246 in the LIFU arm and 123 in the control arm. Secondary outcomes are the best overall response rate and median time-to-response. Exploratory outcomes are median PFS, OS, intracranial PFS, extracranial PFS, and quality of life. Clinical trial information: NCT05317858.
QOL-24. FINANCIAL AID REQUESTS BY BRAIN TUMOR PATIENTS IN ONTARIO THROUGH GOFUNDME
Authors: Kaviya Devaraja, Jonathan Avery, Yajur Iyengar, Andy Zhang, Seth Climans
Journal: Neuro-Oncology (2023)

Abstract Brain tumors affect individuals globally including Ontario residents. Numerous Ontario brain tumor patients suffer the unequal burden of responsibility to pay for treatments like oral chemotherapy. In addition to chemotherapy, patients and their families have other costs associated with their diagnosis. However, less is known about other direct and indirect financial costs due to their diagnosis. GoFundMe, an online fundraising platform, provides worldwide brain tumor patients the opportunity to raise money for financial assistance with costs associated with their diagnosis The purpose of this study was to analyze publicly-available data from GoFundMe, an online fundraising platform, to explore the financial needs of brain tumor patients across Ontario, unaware and/or unable to get assistance elsewhere. A qualitative descriptive design drawing on thematic analysis was used to analyze GoFundMe requests to support individuals diagnosed with brain cancer in Ontario between 2014 and 2021. A coding framework was created to determine emerging themes using qualitative data analysis software NVivo 10. A final sample of 154 requests described financial strain from the loss of income experienced by the patient and their caregivers to afford cancer treatments. Requests highlighted 1) an overall lack of awareness of how and where access financial aid and affordable psychosocial support; 2) concerns over the long-term financial well-being of bereaving family members; 3) A call for more public awareness of the financial burden and emotional distress experienced by of those impacted by brain cancer. These GoFundMe requests highlight a connection between financial burden and emotional distress and an overall lack of awareness of where/how to seek financial and emotional support. These results will serve as the foundation to advocate for and raise awareness of the financial assistance needed by brain tumor patients and their families.
MODL-27. INTEGRATING OVERALL SURVIVAL AND TUMOR CONTROL PROBABILITY MODELS TO PREDICT LOCAL PROGRESSION AFTER BRAIN METASTASIS RADIOSURGERY
Authors: Jeffrey Quezada, Jeremy Harris, Erin Healy, Steven Seyedin, Allen Chen, Jeffrey Kuo, Aaron Simon
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Stereotactic radiosurgery (SRS) for brain metastases has competing goals of maximizing local control and minimizing toxicity. Tumor control probability (TCP) models predict decreasing risk of local progression (LP) with dose escalation. However, many patients die from extracranial disease prior to local progression and may not require maximally aggressive treatment, which increases risk of toxicity. Better tools to assess patients’ risk of LP after SRS could help practitioners personalize SRS treatment to maximize therapeutic ratio. Here we assess whether simultaneous modeling of TCP and overall survival (OS) can improve prediction of LP after SRS. METHODS Records of patients undergoing SRS at a single institution were reviewed retrospectively. Using established OS and TCP models, the probability of one-year survival [p(OS)] and probability of one-year LP [p(LP)]) were calculated for each patient and each metastasis, respectively. Joint-probability was used to combine the models [p(LP,OS)=p(LP)*p(OS)]. Analyses were conducted at the individual-metastasis and whole-patient levels. Fine-Gray regression was used to model the effect of p(LP) or p(LP, OS) on risk of local progression after SRS, with death as a competing risk. RESULTS Ninety-two patients and 391 lesions were identified. At the patient level, one-year LP was 0.08 (95%CI, 0.03-0.15), median p(LP,OS) was 0.13 (95%, CI 0.07-0.2), and median p(LP) was 0.29 (95% CI, 0.22-0.38). At the metastasis level, one-year LP was 0.02 (95%CI, 0.01-0.04), median p(LP,OS) was 0.05 (95%, CI 0.02-0.07), and median p(LP) was 0.10 (95% CI, 0.07-0.13). p(LP,OS) was significantly associated with the risk of local progression at the patient level (p=0.048) and metastasis level (p=0.007); however, p(LP) was not (p=0.16 and p=0.28, respectively). CONCLUSION This study suggests simultaneous OS and TCP modeling more accurately predicts LP than TCP modeling alone. Better understanding which patients are at risk of LP after SRS may help personalize treatment to minimize risk without sacrificing efficacy.
DDDR-33. TNG908, A BRAIN-PENETRANT MTA-COOPERATIVE PRMT5 INHIBITOR, IS EFFICACIOUS IN PRECLINICAL MTAP-DELETED MODELS INCLUDING GLIOBLASTOMA
Authors: Minjie Zhang, Alice Tsai, Kevin Cottrell, Erik Wilker, Charles Davis, Heather DiBenedetto, Ron Weitzman, Alan Huang, John Maxwell, Kimberly Briggs
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The median overall survival (OS) of GBM patients is poor (1-2 years) with standard of care therapies, demonstrating the significant need for the development of novel therapeutics. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that is selectively active in MTAP-deleted cells by leveraging a synthetic lethal interaction. Approximately 40% of GBM tumors have MTAP loss due to a co-deletion event with the proximal tumor suppressor gene, CDKN2A. In preclinical in vitro studies, TNG908 was 15-fold more potent in MTAP-deleted cancer cell lines than in MTAP WT cells. TNG908 has high passive permeability and is neither a substrate for P-glycoprotein nor Breast Cancer Resistant Protein (BCRP) efflux transporters. Consistent with these favorable attributes, TNG908 demonstrated in vivo brain penetration in multiple preclinical models, including non-human primates and mice. TNG908 on-target pharmacodynamic activity was determined by dose-dependent decreases in SDMA-modified protein levels in a GBM subcutaneous xenograft model. TNG908 demonstrated dose-dependent antitumor activity in multiple hyper- and hypomethylated GBM subcutaneous models, including cell lines and patient-derived xenograft models. Despite 6-fold reduced Kpuu in rodents (Kpuu ~0.15) relative to non-human primates (Kpuu 0.9), oral administration of TNG908 drove near tumor stasis and increased median survival by 3-fold in a highly aggressive murine GBM orthotopic model. In summary, TNG908 is a potent, brain-penetrant, MTA-cooperative PRMT5 inhibitor that drives strong antitumor activity in preclinical models of MTAP-deleted GBM. TNG908 is currently enrolling patients with MTAP-deleted tumors including glioblastoma in a Phase I/II clinical trial (NCT05275478).
INNV-07. ADJUVANT POST-SURGERY TREATMENT OF RECURRENT IDH2 MUTANT ANAPLASTIC OLIGODENTROGLIOMA (AO) WITH IDH2 INHIBITOR, ENASIDENIB: A CASE REPORT
Authors: Xiao-Tang Kong, Beverly Dan Fu, Joon Myung, Daniela Bota
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Recent phase III trial presented by Mellinghoff at 2023 ASCO demonstrated successful treatment of Isocitrate dehydrogenase (IDH)–mutant grade 2 gliomas with Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes. Ivosidenib and enasidenib are separate inhibitors of mutant IDH1 and IDH2, which have shown single-agent activity for the treatment of IDH1- or IDH2-mutant acute myeloid leukemia but the effect in the treatment of glioma is uncertain. Here we report a case of IDH2 mutant AO, who was treated with enasidenib for about two years with fair tolerance and was postponed the next intervention. CASE REPORT A 36 yo female was diagnosed anaplastic ogligodentroglioma in 2006, 17 yrs ago. The patient underwent surgery resection, radiation and Temozolomide (TMZ), and 4 cycles of adjuvant TMZ. In 2021, fifteen years later, she was found tumor recurrence. She had a second surgery with near gross total resection. Pathology confirmed anaplastic oligodentraglioma with negative IDH1 mutation but positive IDH2 R172K mutation. To avoid re-radiation nor re-challenge with TMZ, the patient opted IDH2 inhibitor therapy after surgery. The patient tolerated the treatment, and her brain MRI demonstrated no tumor recurrence until one year later when her brain MRI showed vague sub-centimeter nodular non-enhancing lesion at surgical area. Enasidenib was continued for additional 6 months until recent MRI showed small and slow growth. Total therapy is 20 months. Clinically, the patient has no symptoms from tumor. DISCUSSION Our case review found post-surgery therapy with IDH2 inhibitor Enasidenib for IDH2 mutant recurrent AO is tolerated and could postpone next intervention such as re-radiation or re-challenge with TMZ.
RBIO-10. NEUROMODULATORY EFFECT AND DOSE RESPONSE OF FUNCTIONAL RADIOSURGERY ON CORTICAL NEURONS
Authors: Sara Gholampourkashi, Jean-Phillipe Thivierge, Vimoj Nair
Journal: Neuro-Oncology (2023)

Abstract PURPOSE The effects of functional radiosurgery on neuronal circuits remain poorly understood. Neurons of the prefrontal cortex communicate via precisely-timed action potentials that control cognition. Here, we examined the dose response of ablative radiation dose on the patterns of communication of neural circuits in prefrontal acute slices. Materials and METHODS Escalating doses from 20 Gy to 100 Gy of ablative radiation were applied to rodent cortical neurons using the robotic Radiosurgery device (CyberKnife(R) G4). Neuronal communication within irradiated prefrontal slices were compared to control slices (sham radiation); and assessed by plating slices on a multielectrode array that captured high-resolution (18 kHz) extracellular activity across 4,096 channels simultaneously. Comparisons also with recordings of slices treated with a pro-epileptiform solution and finally, correlated with staining for cell death. RESULTS Compared to control slices (mean rate of 0.06 Hz), the post-radiosurgery slices yielded a 40-fold increase in discharge rates (mean rate of 2.87 Hz for 20 Gy, 2.44 Hz for 50 Gy, and 1.95 Hz for 100 Gy radiation). Pearson cross-correlations were computed across all pairs of channels, yielding a matrix of 4,096-by-4,096 interactions. Radiated slices exhibited decreased correlations relative to control slices. A total of 7,446 neuronal interactions were above a threshold correlation of 0.5 in control slices, compared to none following a 20 Gy dose, 50 interactions following a 50 Gy dose and 28 interactions following a 100 Gy dose. Slices treated with pro-epileptiform solution slices yielded large seizure-like events characterized by increased discharge rates and increased pairwise correlations. CONCLUSION Post-radiosurgery slices yielded a unique signature of neuronal activity with increased rates; but with a pronounced decrease in correlations; suggesting diminished communication across neurons to create a neuro-modulatory effect on target tissue; or result in cognitive toxicity on organ-at-risk respectively.
TMIC-22. IDENTIFICATION OF EXOSOME MIRNA-MRNA INTERACTIONS IN THE GLIOMA TUMOR IMMUNE MICROENVIRONMENT
Authors: Emily Xu, Katharine Krueger, Jonathan Sussman, Ebrar Akca, Irina-Mihaela Matache, Amitha Halthore, Jonathan Patterson, Nduka Amankulor
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Exosomes have emerged as key local and systemic immune modulators in glioma, particularly in tumors with an IDH mutation. However, the exact mechanism by which these vehicles communicate with the tumor immune microenvironment warrants further exploration. We sought to identify exosomal miRNA differences in discrete genomic subsets in glioma and predict potential mRNA targets in tumor immune cell populations. METHODS Exosomes were isolated from IDH wild-type (IDHwt) and IDH mutant (IDHm) glioma organoids using ultracentrifugation. Nanoparticle Tracking Analysis and western blot were used to validate exosome capture. Exosomal miRNA was sequenced using the Illumina Novaseq platform and targets were predicted using TargetScan. Peripheral blood mononuclear cells (PBMCs) were isolated from glioma patients and processed for scRNA-seq. RESULTS The characteristics of isolated exosomes were consistent with previously published data. Six miRNAs were over-expressed in IDHm exosomes compared to IDHwt. Interestingly, none of these miRNAs were significantly up-regulated in IDHm tumor tissue. Comparison between predicted targets of IDHm exosome miRNA and scRNA-seq of circulating tumor PBMCs identified a set of expressed genes involved in the FOXO pathway, which is implicated in microglia activation and polarization. Furthermore, scRNA-seq analysis showed that the FOXO3 pathway is activated in CD14+AREG+ monocytes and CD14+RNA-lo monocytes, which are two cell populations that are fractionally down-regulated in IDHm glioma. CONCLUSION Our group and others have defined mutation-dependent mechanisms of immunosuppression in glioma. Here, we characterized the effects of tumor mutational status on exosome miRNA cargo and conducted a miRNA-mRNA network analysis to identify potential targets in tumor-associated myeloid cells. Our results suggest that exosomes may play a role in suppressing specific populations of monocytes via the FOXO pathway in an IDH-mutation dependent manner. This data sets the stage for mechanistic exploration of glioma exosomes on peripheral myeloid tumor immunity.
EPID-27. LIVING NEAR OIL AND GAS WELLS AND MORTALITY IN CHILDREN WITH BRAIN TUMORS
Authors: Thanh Hoang, Rutu Rathod, Jeremy Schraw, Erin Peckham-Gregory, Philip Lupo, Amy Hughes, Michael Scheurer
Journal: Neuro-Oncology (2023)

Abstract METHODS: The heating profile of MIONPs was assessed in the test tube and mouse brain in vivo. Computed tomography scan and magnetic particle imaging were used to confirm intracranial MIONP localization after convection enhanced delivery. Cell viability assays were performed following treatment with MHT and/or radiation. MHT-induced alterations to the tumor microenvironment were assessed in a syngeneic murine glioma model, and a survival study was performed in a GBM patient-derived xenograft (PDX) model to investigate synergism between MHT and CRT.
PATH-31. RECURRENT COPY NUMBER CHANGES IN GLIOBLASTOMA, IDH-WILDTYPE: ARE OTHER +7/-10 PATTERNS CLINICALLY RELEVANT?
Authors: Lauren Choate, Vanessa Pazdernik, Thomas Kollmeyer, Corinne Praska, Robert Jenkins, Cristine Ida
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM), IDH-wildtype (WT) is currently defined as an IDH-WT and H3-WT diffuse astrocytic glioma with molecular diagnostic features including whole +7/−10, TERT promoter (TERTp) mutation, and EGFR amplification and/or morphological diagnostic features such as necrosis and microvascular proliferation. To further understand the diversity of copy number signatures of GBM, IDHWT and evaluate the diagnostic utility of other recurrent copy number changes, we analyzed paired chromosomal microarray and next-generation sequencing mutational profiling data from 418 adult IDH-WT and H3-WT tumors with GBM morphological diagnostic features. The most common molecular features were TERTp mutations (85%), CDKN2A/B heterozygous/homozygous deletion (78%/66%), +7/-10 (63%), EGFR amplification (41%), +19 (36%), PTEN mutations (35%), partial -13 (33%), partial -14 (33%), +20 (32%), TP53 mutations (32%), and partial -22 (29%). At least one molecular diagnostic biomarker was present in 92% (n=385) of cases, and 29% (n=121) of cases had all three. The +7/-10 biomarker was the most frequent chromosomes 7/10 copy number change (68%, n=265). Other +7/-10 patterns were seen in 30% (n=125) of cases and included isolated +7 or -10, combinations of +7 and -10 with partial +7, partial -10 or 10 copy neutral loss of heterozygosity (cnLOH). Overall, 93% (390/418) of cases had whole and other chromosome 7/10 copy number changes. In comparison to tumors with +7/-10, tumors with other +7/-10 patterns were significantly enriched for partial 13 loss (Bonferroni adjusted p=0.04) but were not associated with significant difference in patient overall survival (p=0.30, 158/418 had available survival data). Our findings reiterate and expand the spectrum of copy number changes associated with GBM, IDH-WT. The similar overall survival rates between cases with the +7/-10 biomarker and those with other +7/-10 patterns suggest that other +7/-10 patterns may be functionally equivalent to +7/-10 and diagnostically relevant as a molecular diagnostic biomarker for this tumor type.
EXTH-83. BIRC3 AS A PREDICTOR OF OUTCOME AND A NEW THERAPEUTIC TARGET IN TMZ RESISTANT GLIOBLASTOMA TUMORS
Authors: Mariangela Morelli, Sara Franceschi, Francesca Lessi, Paolo Aretini, Aldo Pastore, Elena Corradi, Andrea Marranci, Carlo Gambacciani, Francesco Pieri, Gianluca Grimod, Nicola Montemurro, Manuel Giacomarra, Michele Menicagli, Gianmarco Ferri, Francesco Pasqualetti, Marc Sanson, Alberto Picca, Anna Luisa Di Stefano, Orazio Santo Santonocito, Chiara Maria Mazzanti
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is an incurable malignant brain tumor, with a highly unfavorable prognosis. Apart from MGMT promoter methylation and TMZ response, molecular biomarkers associated with therapeutic response or survival prognosis are still lacking in GBM. Previously, using NAD(P)H-fluorescence lifetime imaging, a new drug screening precision medicine ex-vivo approach, we perturbed patients-derived vital GBM tumor explants (GB-EXPs) by TMZ treatment and obtained a stratification in TMZ responder (Res) and non-responder (Non-Resp) tumors, identifying several genes differentially expressed between the two groups. To validate the approach we enlarged our glioblastoma case study. Transcriptome analysis was performed to characterize TMZ Res and Non-Resp cases. In-silico and functional cellular investigations were carried on to explore the biomarker's efficiency. The majority of the genes found dysregulated in the previous study, showed the same directional regulation of expression and we confirmed, in TMZ-resistant samples the statistically significant upregulation of BIRC3, a strong inhibitor of apoptosis. The TCGA dataset provided an opportunity to fully assess the BIRC3 mRNA expression complementarity with the MGMT status as a predictor of outcome. BIRC3 was validated as a prognostic factor of survival also in large French and Italian glioblastoma cohorts. Most importantly, AZD5582 drug, which is a specific antagonist of BIRC3, combined with TMZ treatment, is able to reverse the TMZ resistance, in glioblastoma cell lines, by restoring apoptosis, and in GB-EXPs that were resistant to TMZ treatment. BIRC3 represents a potential biomarker of prognosis and a predictor of TMZ treatment response in GBM and complements MGMT status as an outcome predictor. The level of BIRC3 expression could stratify patients who will benefit from AZD5582 or its combination with TMZ. Our study provides a potentially new treatment approach and valuable leads to determine whether functional precision medicine combined with BIRC3 expression assessment become a standard tool in glioblastoma clinical oncology.
QLTI-03. FRACTIONATED PREOPERATIVE VS POSTOPERATIVE STEREOTACTIC RADIOTHERAPY FOR PATIENTS WITH MELANOMA BRAIN METASTASES: A COST UTILITY ANALYSIS
Authors: Alexander Keister, Joshua Vignolles-Jeong, Daniel Kreatsoulas, Mark Damante, J Bradley Elder
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Stereotactic radiosurgery (SRS) followed by surgical resection is an emerging treatment paradigm for brain metastases. Preoperative SRS may improve outcomes such as rates of radiation necrosis (RN) and leptomeningeal disease (LMD) compared to postoperative SRS. However, the impact of this paradigm shift on metrics such as cost of care and hospital length of stay is unclear. In this study, we sought to categorize these metrics for melanoma metastases, specifically. METHODS A retrospective analysis identified patients who underwent surgical resection and fractionated stereotactic radiation therapy (FSRT) for melanoma brain metastases. Demographics, medical history, systemic and local treatment modalities, imaging, and postoperative course were collected. Perioperative cost of care was analyzed beginning two weeks preoperatively and concluded at four-weeks postoperatively. Continuous variables were analyzed via non-parametric two-sided t-tests and ANOVAs. Categorical variables were analyzed via Chi-squared tests. RESULTS Forty-two patients underwent 43 craniotomies for melanoma metastases. The mean age at surgery was 59.6 years-old and the male predominance was 65.1%. Total cost of perioperative care was more expensive among those treated with neoadjuvant (n = 11) FSRT compared to those who underwent postoperative (n = 32) FSRT ($262,072 vs $174,646; p = 0.0254). Mean length of stay for craniotomies was similar between groups (p = 0.1674), although trending down among the neoadjuvant FSRT group (4.5 days) among the neoadjuvant FSRT group versus the postoperative FSRT group (7.0 days). CONCLUSIONS In this study, neoadjuvant FSRT had an increased cost of care in the perioperative period, and similar lengths of hospital stay for craniotomy. Preoperative FSRT for melanoma metastases may result in shorter LOS, however, comes with an increased cost of care. Further investigation of itemization of healthcare costs to identify areas of improvement for neoadjuvant therapy is warranted.